TY - JOUR
T1 - Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer
AU - Ni, Yingjia
AU - Schmidt, Keon R.
AU - Werner, Barnes A.
AU - Koenig, Jenna K.
AU - Guldner, Ian H.
AU - Schnepp, Patricia M.
AU - Tan, Xuejuan
AU - Jiang, Lan
AU - Host, Misha
AU - Sun, Longhua
AU - Howe, Erin N.
AU - Wu, Junmin
AU - Littlepage, Laurie E.
AU - Nakshatri, Harikrishna
AU - Zhang, Siyuan
N1 - Funding Information:
This work was supported by the Department of Defense through the Breast Cancer Research Program under Award W81XWH-18-1-0473. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. This work was partially supported by NIH R01 CA194697-01 (S.Z.), NIH R01 CA222405-01A1 (S.Z.), and NIH CTSI core facility pilot grants (S.Z.). We would additionally like to acknowledge and thank the Dee Family endowment (S.Z.). We would also like to thank Zhang Lab members for scientific insight and support. For insightful technical assistance, we thank Charles R. Tessier, Ph.D. We would also like to thank Dr. Nakshatri (IUSM) for offering precious KTB cell lines and intellectual discussions of the manuscript. For PDX samples, we would like to thank Dr. Littlepage (ND) for offering tumor samples and Dr. Welm (Utah) for tremendous efforts in establishing PDX model. We are additionally grateful for the use of the following core facilities: Notre Dame Genomics and Bioinformatics Core Facility, Notre Dame Frei-mann Life Sciences Center, Harper Cancer Research Institute Biorepository, Indiana University School of Medicine South Bend Imaging and Flow Cytometry Core, KTB, and Indiana University Simon Cancer Center Core Facility.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Lacking targetable molecular drivers, triple-negative breast cancer (TNBC) is the most clinically challenging subtype of breast cancer. In this study, we reveal that Death Effector Domain-containing DNA-binding protein (DEDD), which is overexpressed in > 60% of TNBCs, drives a mitogen-independent G1/S cell cycle transition through cytoplasm localization. The gain of cytosolic DEDD enhances cyclin D1 expression by interacting with heat shock 71 kDa protein 8 (HSC70). Concurrently, DEDD interacts with Rb family proteins and promotes their proteasome-mediated degradation. DEDD overexpression renders TNBCs vulnerable to cell cycle inhibition. Patients with TNBC have been excluded from CDK 4/6 inhibitor clinical trials due to the perceived high frequency of Rb-loss in TNBCs. Interestingly, our study demonstrated that, irrespective of Rb status, TNBCs with DEDD overexpression exhibit a DEDD-dependent vulnerability to combinatorial treatment with CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo. Thus, our study provided a rationale for the clinical application of CDK4/6 inhibitor combinatorial regimens for patients with TNBC.
AB - Lacking targetable molecular drivers, triple-negative breast cancer (TNBC) is the most clinically challenging subtype of breast cancer. In this study, we reveal that Death Effector Domain-containing DNA-binding protein (DEDD), which is overexpressed in > 60% of TNBCs, drives a mitogen-independent G1/S cell cycle transition through cytoplasm localization. The gain of cytosolic DEDD enhances cyclin D1 expression by interacting with heat shock 71 kDa protein 8 (HSC70). Concurrently, DEDD interacts with Rb family proteins and promotes their proteasome-mediated degradation. DEDD overexpression renders TNBCs vulnerable to cell cycle inhibition. Patients with TNBC have been excluded from CDK 4/6 inhibitor clinical trials due to the perceived high frequency of Rb-loss in TNBCs. Interestingly, our study demonstrated that, irrespective of Rb status, TNBCs with DEDD overexpression exhibit a DEDD-dependent vulnerability to combinatorial treatment with CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo. Thus, our study provided a rationale for the clinical application of CDK4/6 inhibitor combinatorial regimens for patients with TNBC.
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U2 - 10.1038/s41467-019-10743-7
DO - 10.1038/s41467-019-10743-7
M3 - Article
C2 - 31253784
AN - SCOPUS:85068153495
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2860
ER -